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Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells

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Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells International Journal of Molecular Sciences Article Phenolic Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Dysfunction and Suppress Acute Lymphoblastic Leukemia Cells Miguel Olivas-Aguirre , Liliana Torres-López , Igor Pottosin * and Oxana Dobrovinskaya * Laboratory of Immunobiology and Ionic Transport Regulation, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Villa de San Sebastián, 28045 Colima, Mexico; [email protected] (M.O.-A.); [email protected] (L.T.-L.) * Correspondence: [email protected] (I.P.); [email protected] (O.D.) Abstract: Anticancer activity of different phenols is documented, but underlying mechanisms remain elusive. Recently, we have shown that cannabidiol kills the cells of acute lymphoblastic leukemia (ALL) by a direct interaction with mitochondria, with their consequent dysfunction. In the present study, cytotoxic effects of several phenolic compounds against human the T-ALL cell line Jurkat were tested by means of resazurin-based metabolic assay. To unravel underlying mechanisms, 2+ mitochondrial membrane potential (DYm) and [Ca ]m measurements were undertaken, and reactive oxygen species generation and cell death were evaluated by flow cytometry. Three out of eight tested phenolics, cannabidiol, curcumin and quercetin, which displayed a significant cytotoxic 2+ effect, also dissipated the DYm and induced a significant [Ca ]m increase, whereas inefficient phenols did not. Dissipation of the DYm by cannabidiol was prevented by cyclosporine A and reverted by Ru360, inhibitors of the permeation transition pore and mitochondrial Ca2+ uniporter, 2+ respectively. Ru360 prevented the phenol-induced [Ca ]m rise, but neither cyclosporine A nor Ru360 affected the curcumin- and quercetin-induced DYm depolarization. Ru360 impeded the curcumin- Citation: Olivas-Aguirre, M.; and cannabidiol-induced cell death. Thus, all three phenols exert their antileukemic activity via Torres-López, L.; Pottosin, I.; mitochondrial Ca2+ overload, whereas curcumin and quercetin suppress the metabolism of leukemic Dobrovinskaya, O. Phenolic cells by direct mitochondrial uncoupling. Compounds Cannabidiol, Curcumin and Quercetin Cause Mitochondrial Keywords: acute lymphoblastic leukemia; cannabidiol; curcumin; quercetin; mitochondria; cytotoxi- Dysfunction and Suppress Acute city Lymphoblastic Leukemia Cells. Int. J. Mol. Sci. 2021, 22, 204. https://dx. doi.org/10.3390/ijms22010204 1. Introduction Received: 29 November 2020 Accepted: 23 December 2020 Cancer represents a main cause of morbidity and mortality worldwide. Acute lym- Published: 28 December 2020 phoblastic leukemia (ALL) is an aggressive hematologic disorder that occurs mainly in children and adolescents. T-lineage ALL (T-ALL) represents a clinical challenge due its mul- Publisher’s Note: MDPI stays neu- tiple mechanisms of chemotherapy resistance and cell death evasion, responsible for patient tral with regard to jurisdictional claims chemotherapy failure, relapse and death [1,2]. Therefore, the search for novel antileukemic in published maps and institutional compounds with a high anticancer effectiveness and low side effects continues. affiliations. Phenolic compounds are a group of phytochemicals, containing one or several aro- matic rings, which are commonly obtained from plants, vegetables and common beverages such as beer, red wine or coffee. They received attention primarily due to their antioxi- dant activity. Yet, phenolic compounds possess a broader spectrum of action, including Copyright: © 2020 by the authors. Li- cytotoxic effects in different cancer types [3–5]. Previous studies have suggested that high censee MDPI, Basel, Switzerland. This article is an open access article distributed consumption of phenols may reduce cancer risks. Related mechanisms include, but are not under the terms and conditions of the restricted to, modifications in the antioxidant system, receptor-mediated cell signaling, cell Creative Commons Attribution (CC BY) cycle modifications and cell death induction. Importantly, the anticancer effect of phenols license (https://creativecommons.org/ seems to be highly dependent on phenol species and cancer type [6]. licenses/by/4.0/). Int. J. Mol. Sci. 2021, 22, 204. https://dx.doi.org/10.3390/ijms22010204 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 204 2 of 13 Antileukemic activity was demonstrated for several phenolic compounds, albeit precise step-by-step mechanisms remain elusive. Reported effects include a decrease in cancer cells population in vitro and in vivo, deregulation of the Bcl-2 protein ratio, caspase activation, reactive oxygen species (ROS) production, cytochrome c release and apoptosis induction (Table S1). Recently, targeting to mitochondria, which provokes their dysfunction, was demon- strated for several small molecules containing phenolic groups, such as ellagic acid, cur- cumin, aspirin and cannabidiol (CBD) [7–10]. Several phenols with a pKa within the physiological range possess protonophore activity, thus efficiently dissipating the elec- trochemical gradient for H+ across the inner mitochondrial membrane and, in this way, suppressing different cancer cell types [11]. Notably, leukemic mitochondria have been proposed as an attractive target for anticancer therapy. Mitochondria acquire different al- terations during malignant reprogramming that make them susceptible to small molecules with anticancer activity, known as mitocans, which include phenolic compounds [12,13]. We have recently demonstrated that CBD, a main phytocannabinoid derived from Cannabis spp., kills leukemic cells by directly targeting mitochondria and causing ROS 2+ generation, mitochondrial calcium ([Ca ]m) overload, stable mitochondrial permeability transition pore (mPTP) formation and cytochrome c release, which eventually promotes apoptosis and mPTP-driven necrosis [10]. Western blot data and experiments with isolated voltage-dependent anion channel (VDAC) protein, incorporated into a planar lipid bilayer, demonstrated that CBD directly interacts with and switches VDAC to a closed conforma- tional substate [14]. A similar mechanism was also reported for curcumin and aspirin and is considered to be the cause of the tumor cell death [8,9]. VDAC is unique porin, functionally present and abundant in the outer mitochondrial membrane. It acts as the mitochondrial gatekeeper, mediating ionic and metabolic fluxes between the cytosol and the mitochon- drial intermembrane space [15–17]. The selectivity of this exchange critically depends on the conformational state of VDAC. The aforementioned closed conformational substate is impermeable for large metabolites like adenine nucleotides, but highly permeable to Ca2+ [15]. The combination of these two factors can eventually lead to mitochondrial Ca2+ overload [10]. The purpose of the present work was to test the cytotoxic effects of several phenolic compounds with a documented antileukemic activity, using the human Jurkat cell line as a model for acute lymphoblastic leukemia of T type (T-ALL). Specifically, we wish to unravel whether the anti-T-ALL activity of the phenolics is correlated with their effects on ROS generation and alterations of the mitochondrial parameters, such as electrical potential difference and Ca2+ homoeostasis, and whether the prevention of the latter can revert the cytotoxicity. 2. Results 2.1. Comparison of Antileukemic Properties of Different Phenolic Compounds in T-ALL Model Eight phenol-containing compounds that were reported earlier to possess cytotoxic properties against different types of leukemia (Table S1) were selected to compare their antileukemic potential against T-ALL-derived Jurkat cells. A metabolic activity assay showed that CBD and curcumin were the most cytotoxic, with an IC50 of 12.1 and 36.5 µM, respectively (Figure1). Chlorogenic and gallic acid, as well as quercetin, exhibited a mild cytotoxicity, whereas aspirin, methyl gallate and protocatechuic acid at concentrations up to 2.5 mM lacked any substantial effect at 24 h. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 12 Int. J. Mol. Sci. 2021, 22, 204 3 of 13 Figure 1. Cytotoxic effect of phenols on leukemic cells. (a–f) Cytotoxic effect of phenolic compounds was estimated by Figure 1.means Cytotoxic of resazurin-based effect of phenols metabolic on assay. leukemic T-ALL cells. cells (Jurkat)(a–f) Cytotoxic were incubated effect inof the phenolic presence compounds or absence of was aspirin estimated (a), by means ofcannabidiol, resazurin-based CBD (b ),metabolic chlorogenic assay. acid (T-ALLc), curcumin cells ((Jurkatd), gallic) were acid ( eincubated), methyl gallate in the (f presence), protocatechuic or absence acid ( gof) andaspirin (a), cannabidiol,quercetin CBD (h ),(b for), 24chlorogenic h. Resorufin acid fluorescence (c), curcumin was measured (d), gallic and normalized acid (e), methyl to untreated gallate cells. ( Dataf), protocatechuic are mean ± SD (acidn = 9 (g) and quercetinfrom (h), three for independent24 h. Resorufin experiments; fluorescence * p < 0.05; was ** pmeasured< 0.01; *** pand< 0.001; normalized **** p < 0.0001; to untreated one-way ANOVA). cells. Data Non-linear are mean fit of± SD (n = 9 from threethe dose-dependence independent experiments; yields the following * p < 0.05; IC50 values** p < 0.01; (in µM): *** 12.1p < for0.001; CBD **** and p 36.5< 0.0001; for curcumin. one-way ANOVA). Non-linear fit of the dose-dependence yields the following IC50 values (in µM): 12.1 for CBD and 36.5
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